Obesity, defined as an excess of body fat relative to lean body mass, contributes to and complicates other diseases. For example, obesity substantially increases the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, as well as cancers of the endometrium, breast, prostate and colon. As a major cause of preventable death in the United States today, obesity poses a major public health challenge.
Overweight is defined today as a body mass index (BMI) of 25-29.9 kg/m2, and obesity is defined as a BMI>30 kg/m2. Over 60% of the adult population of the United States and Australia are either overweight (BMI of 25-29.9 kg/m2) or obese (BMI>30 kg/m2). More than 20% of adults fall into this latter category.
The cause of obesity is quite complex and not merely the result of voluntary overeating. Rather, the differential body composition observed between obese and normal subjects results from differences in both metabolism and neurologic/metabolic interactions.
The purpose of weight loss and weight maintenance is to reduce health risks. If weight is regained, health risks increase. A majority of patients who lose weight regain it, so the challenge to the patient and the practitioner is to maintain weight loss. Because of the tendency to regain weight after weight loss, the use of long-term medication to aid in the treatment of obesity may be indicated for carefully selected patients.
The drugs used to promote weight loss are traditionally anorexiants or appetite suppressants. Three classes of anorexiant drugs have been developed, all of which affect neurotransmitters in the brain. They may be designated as follows: (1) those that affect catecholamines, such as dopamine and norepinephrine; (2) those that affect serotonin; and (3) those that affect more than one neurotransmitter. These drugs work by increasing the secretion of dopamine, norepinephrine, or serotonin into the synaptic neural cleft, by inhibiting the reuptake of these neurotransmitters into the neuron, or by a combination of both mechanisms. Sibutramine inhibits the reuptake of norepinephrine and serotonin. Orlistat is not an appetite suppressant and has a different mechanism of action; it blocks about one-third of fat absorption.
Weight loss drugs approved by the FDA for long-term use may be useful as an adjunct to diet and physical activity for patients with a BMI>27 who also have concomitant obesity-related risk factors or diseases. Our thinking about drug therapy has undergone radical changes over the past few years.
Of recent interest as a target has been the melanocortin receptor family. The term melanocortin (“MC”) defines a family of peptide hormones that regulate diverse physiological functions through transmembrane G-protein coupled receptors. Melanocortins include melanocyte-stimulating hormones (MSH) such as α-MSH, β-MSH and γ-MSH, as well as adrenocorticotropic hormone (ACTH). The melanocortin (MC) receptors (“MCRs”) are a group of cell surface proteins that mediate a variety of physiological effects, including adrenal gland function, production of cortisol and aldosterone, control of melanocyte growth and pigment production, thermoregulation, immunomodulation and analgesia. In the past several years, five distinct melanocortin receptor subtypes have been identified. The five MC receptors, termed MCR1, MCR2, MCR3, MCR4 and MCR5, all couple in a stimulatory fashion to cAMP. MCR1, MCR3, MCR4 and MCR5 constitute subtypes of MSH receptors. The MCRs stimulate adenyl cyclase to generate cAMP.
The MC1 receptor is present on melanocytes and melanoma and is involved in skin pigmentation. The MCR2 receptor is the ACTH receptor and is present predominantly in the adrenal gland. MCR2 plays a role in adrenal steroidogenesis. The mRNA for the MCR3 receptor has been found in the brain, as well as in placental and gut tissues. The MCR4 receptor has been found primarily in the brain. The MCR5 receptor is expressed in the brain, as well as in several peripheral tissues and has been implicated in exocrine gland function.
The melanocortin peptides also mediate a number of other physiological effects. They are reported to affect motivation, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, brain blood flow, nerve growth and repair, placental development, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual activity, penile erection, blood glucose levels, intrauterine fetal growth, food motivated behavior, as well as other events related to parturition.
Recently, MC receptor MCR4 has been shown to function in the regulation of body weight and food intake. Early studies on mice that expressed agouti ectopically, which is a MCR4 antagonist, produced obese animals. Subsequent work has shown that MCR3 and MCR4 antagonists stimulated food intake and that MCR4 knockout mice are obese. Synthetic MC4 agonist peptides that mimic melanocortins and bind to MCR4 injected into the brain, cause suppression of feeding in normal and mutant obese mice. Targeted disruption of MCR4 causes mice to develop a maturity onset of obesity associated with hyperphagia, hyperinsulinemia and hyperglycemia (Huszar et al., supra). Stimulation of the MC4 receptor by an endogenous ligand, α-MSH, produces a satiety signal and may be the downstream mediator of the leptin signalling pathway. These results indicate that the brain MC receptor MCR-4 functions in regulating food intake and body weight and is a promising target in the treatment of obesity. It is believed that by providing potent MC-4 receptor agonists, appetite may be suppressed and weight loss benefits may be achieved. See J. Wikberg, Eur. J. Pharm., 375, 295-310 (1999).
Melanotan II (MTII) is an α-MSH peptide superagonist for MCR4. (M. Hadley et al., Discovery and Development of Novel Melanogenic Drugs, Integration of Pharmaceutical Discovery and Development: Case Studies, Borchardt et al., ed., Plenum Press, New York 1998). Other cyclic and linear α-MSH peptides also have been studied. See, for example, C. Haskell-Luevano et al., J. Med. Chem., 40, 2133-39 (1997); H. Schiöth et al., Brit. J. Pharmacol, 124, 75-82 (1998); H. Schiöth et al., Eur. J. Pharmacol., 349, 359-66 (1998); M. Hadley et al., Pigment Cell Res., 9, 213-34 (1996); M. Bednarek et al., Peptides, 20, 401-09 (1999); and U.S. Pat. Nos. 6,054,556, 6,051,555 and 5,576,290.
WO 98/11128, published 19 Mar. 1998, describes phenylalanine derivatives.
WO 00/78317, published 28 Dec. 2000, describes piperidine derivatives as integrin receptor antagonists. EP 1086947, published 29 Aug. 2000, describes piperidine compounds as agonists and antagonists for the SST receptor. WO 00/35874, published 22 Jun. 2000, describes arylpiperidine compounds as intermediates for the preparation of 5HT1A agonists and antagonists. WO 00/35875, published 22 Jun. 2000, describes arylpiperidine compounds as intermediates for the preparation of 5HT1A agonists and antagonists. WO00/25786, published 11 May 2000, describes substituted piperidines as potassium channel inhibitors. U.S. Pat. No. 5,518,735, issued May 21, 1996, describes phenylalanine derivatives which prevent coagulation or thrombosis. WO 97/19908, published 5 Jun. 1997, describes phenylalanine derivatives as fungicides. WO 97/49673, published 31 Dec. 1997, describes phenylalanine derivatives as thrombin inhibitors.
WO 95/34311, published 21 Dec. 1995, describes substituted piperazine compounds as growth hormone releasing agents. U.S. Pat. No. 5,681,954, issued Oct. 28, 1997, describes substituted piperazines as inhibitors of calmodulin. WO 97/03060, published 30 Jan. 1997, describes piperazine derivatives as cysteine protease inhibitors. U.S. Pat. No. 6,057,290, issued May 2, 2000, describes piperazine derivatives as cysteine protease inhibitors. WO 97/19919, published 5 Jun. 1997, describes sulfonamides as having anti-thrombin activity. U.S. Pat. No. 5,244,895, issued Sep. 14, 1993, describes piperazine derivatives as antiulcer agents. EP 513691, published 31 Jul. 1996, describes piperazine derivatives as antiulcer agents. U.S. Pat. No. 5,244,895, issued Sep. 14, 1993, describes sulfonamides having smooth muscle relaxation activity. WO 94/05693, published 17 Mar. 1994, describes piperazinyl-phenylalanine derivatives as tachyquinine antagonists. J. Sturzebecher et al. J. Enzyme Inhib., 9, 87-99 (1995), describes piperazinyl-phenylalanine derivatives as thrombin inhibitors. M. Böhm et al. J. Med. Chem., 42, 458-77 (1999), describes piperazinyl-phenylalanine derivatives as thrombin inhibitors. J. Sturzebecher et al., J. Med. Chem., 40, 3091-99 (1997), describes piperazinyl-phenylalanine derivatives as thrombin inhibitors. H. Sakamoto, et al. Pept. Chem., 27, 375-8 (1989) describes piperazinyl-phenylalanine derivatives as chymotrypsin inhibitors. H. Sakamoto, et al., Bull. Chem. Soc. Jpn., 64, 2519-23 (1991) describes piperazinyl-phenylalanine derivatives as chymotrypsin inhibitors. G. Wagner, et al., Pharmazie, 36, 597-603 (1981), describes piperazinyl-phenylalanine derivatives as serine protease inhibitors. E. J. Jacobsen et al. J. Med. Chem., 42, 1525-36 (1999) describes thiazolyl ureas as stromelysin inhibitors. WO97/40031, published 30 Oct. 19978, describes thiazolyl ureas as metalloprotease inhibitors.
WO 01/10842, published 15 Feb. 2001, describes melanocortin receptor binding compounds. WO 99/64002, published 16 Dec. 1999, describes spiropiperidines as melanocortin receptor agonists. WO 00/74679, published 14 Dec. 2000, describes piperidine compounds as melanocortin receptor agonists.
However, compounds of the current invention have not been described as inhibitors of MCRs such as for the treatment of obesity.